Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry.

The Hemostasis and Thrombosis Research Society (HTRS) Registry was used to monitor the postapproval use of recombinant factor VIIa. The objective of this manuscript is to provide key insights on the demographics of patients with acquired hemophilia in the HTRS Registry. Acquired hemophilia patient registration in HTRS captured age; sex; comorbidities and predisposing conditions; first bleeding location; laboratory parameters; exposure to blood products, factor, and bypassing agents; and initiation of immune suppression/tolerance therapy. Overall, 166 patients with acquired hemophilia were registered in HTRS (83 women, 73 men, median age 70 years); the majority were non-Hispanic whites (61.4%). The most common comorbidities were autoimmune disease (28.4%) and malignancy (14.5%). The most common first site of bleeding was subcutaneous (27.1%); this was more common in whites (29.1%) than blacks (12.5%) and in non-Hispanics (26.4%) than Hispanics (11.8%). Blood product exposure was reported for 33.1% of patients; the most commonly reported product was packed red blood cells (28%). Of the 57 patients with outcome data available for immune tolerance therapy, 26 patients (46%) reported successful treatment, 13 reported unsuccessful treatment (23%), and 18 (32%) were receiving active treatment at the time of registration. The HTRS Registry final analysis provides the only current comprehensive look at acquired hemophilia in the US population, including details on underlying autoimmune diseases and malignancies. Pertinent to recognition and diagnosis of the disease, subcutaneous bleeding as a presenting bleeding symptom was more common in white and non-Hispanic individuals.

Assessment of the F9 genotype-specific FIX inhibitor risks and characterisation of 10 novel severe F9 defects in the first molecular series of Argentinian patients with haemophilia B.

In haemophilia B (HB) (factor IX [FIX] deficiency), F9 genotype largely determines clinical phenotype. Aimed to characterise Argentinian families with HB, this study presents F9 genotype frequencies and their specific FIX inhibitor risk and 10 novel F9 mutations. Ninety-one DNA samples from HB patients and relatives were subjected to a new scheme: a primary screen for large deletions, a secondary screen for point mutations using conformation sensitive gel electrophoresis, DNA-sequencing and bioinformatic analysis. Our unbiased HB population (N=52) (77% with severe, 11.5% moderate and 11.5% mild HB) showed 32 missense (61.5%), including three novel mutations predicting specific structural/functional defects in silico , seven nonsense (13.5%) (one novel), five large deletions, four splice including three novel mutations affecting predicted splicing scores, three indels (two novel) and one Leiden mutation. Our comprehensive HB population included five patients with long-lasting FIX inhibitors: three nonsense (p.E35* (novel), p.R75*, p.W240*) and two entire- F9 deletions. Another patient with an indel (p.A26Rfs*14) developed transient inhibitors. A case-control analysis, based on our global prevalence of 3.05% for developing inhibitors in HB revealed that missense mutations were associated with a low risk odds ratio (OR) of 0.05 and a prevalence of 0.39%, whereas nonsense and entire- F9 deletions had significantly higher risks (OR 11.0 and 32.7) and prevalence (14.3% and 44.5%, respectively). Our cost-effective practical approach enabled identification of the causative mutation in all 55 Argentine families with HB, analysis of the molecular pathology of novel F9 defects and determination of mutation-associated FIX inhibitor risks.